KIR3DS1 is presumed to be an NK cell activation receptor. The gene has many inhibitory alleles, known as KIR3DL1. Various KIR3DL1 subtypes have been shown to interact directly with HLA-I proteins with the Bw4 public epitope. Regardless of its similarity to KIR3DL1, and its established role in HIV disease, KIR3DS1 no direct ligand of this receptor has been identified. We continue to dissect the biochemical basis of the apparent lack of KIR3DS1 binding to HLA-Bw4. KIR3DL1 binds to HLA-Bw4 but the highly related KIR3DS1 does not. Therefore, we have carried out targeted mutagenesis that defines the residues controlling KIR3DL1/HLA-Bw4 binding by collaborating with a group that solved the crystal structure of KIR3DL1. Using the information gained from these studies we predicted peptides that might facilitate binding of KIR3DS1 by Bw5. We tested multiple peptides and identified 3 that work. These peptides represent the first demonstration of direct interaction between Bw4 and KIR3DS1. In addition to our work on KIR3DL1/S1 we begun to extend this analysis to KIR3DL2, a related receptor implicated in ankylosing spondylitis and cutaneous lymphoma. We have described differential expression of some KIR3DL2 alleles and are working with collaborators in connecting these alleles to disease. In addition, we are beginning study of the biochemistry of KIR3DL2 signaling and function.